The purpose of this project is to define the mechanisms responsible for the regulation of intestinal lactase in health and in common primary and secondary deficiency states. The biology of lactase is unique in respect to the genetically programmed decline in lactase activity that accompanies maturation to adulthood in most of the world's population. An initial objective is the characterization of the cellular and molecular events that dictate lactase persistence or primary deficiency. Because lactase activity is variable from intestinal crypt to villous as well as from proximal to distal small intestine, the definition of these specific regulatory events requires attention to the spatial aspects of lactase expression. Accordingly, the study design will incorporate the techniques of tissue immunocytochemistry and in situ hybridization of tissue mRNA and their application over the entire longitudinal axis of the intestine to achieve the initial objective. In addition to genetic control of lactase activity, expression of the protein is particularly sensitive to mucosal inflammatory changes and alterations of the intraluminal environment. The regulation of lactase expression in the setting of treated celiac disease and intestinal bacterial overgrowth will be examined to provide insight into the nature of secondary lactase deficiency. Finally, a model system using intestinal explants in organ culture to study the modulation of lactase expression in response to changes in the local environment is proposed. The hypothesis that intestinal cytokines play a role in the selective suppression of lactase expression in response to inflammation will be tested.